Synthesis and cytotoxic activity of 1,5,6,7-tetrahydroindol-4-one derivatives and its thio analogue

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Abstract

Derivatives of 1,5,6,7-tetrahydroindol-4-one and its thio analogue were synthesized and their cytotoxicity against HEK293, Jurkat and MCF-7 cells was investigated in vitro. The hit compound, 6,6-dimethyl-1-(2-methylphenyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one, was found to inhibit the metabolic activity of lymphoblastic leukemia cells (Jurkat) with IC50 = 14.8 µM and normal human embryonic kidney cells (HEK293) with IC50 = 93.63 µM. The proposed mechanism of cytotoxic action of the most active compound was shown in silico to be mediated by interaction with the cyclin-dependent kinase CDK9 site.

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About the authors

V. A. Sorokina

Ufa Federal Research Center of the Russian Academy of Sciences

Author for correspondence.
Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0001-5311-9580

Ufa Institute of Chemistry

Russian Federation, Ufa

D. O. Tsypyshev

Ufa Federal Research Center of the Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0003-4551-0226

Ufa Institute of Chemistry

Russian Federation, Ufa

A. V. Koval’skaya

Ufa Federal Research Center of the Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0001-7772-2894

Ufa Institute of Chemistry

Russian Federation, Ufa

V. A. Vakhitov

Ufa Federal Research Center of the Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0001-8805-9872

Institute of Biochemistry and Genetics

Russian Federation, Ufa

I. P. Tsypysheva

Ufa Federal Research Center of the Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0002-5025-8742

Institute of Biochemistry and Genetics

Russian Federation, Ufa

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2. Fig. 1. Evaluation of the effect of compound 3 on cell cycle progression of HEK293, MCF-7, and Jurkat cells. Cells with the test compound at the IC50 concentration determined for each cell line were incubated for 24 (a), 48 (b), 72 hours (c). Data obtained from two independent experiments (N = 2, n = 6) are presented as mean ± standard deviation; * – p < 0.05 (Wilcoxon t-test).

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3. Fig.2. Docking poses of derivative 3 (a) and reference ligand S-CR8 (b) at the 3LQ5 CDK9 binding site; hydrogen bonds are indicated by dotted lines.

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4. Scheme 1.

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5. Scheme 2.

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6. Scheme 3.

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